Cafedrine/Theodrenaline in Anaesthesia Influencing Factors in Restoring Arterial Blood Pressure

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Anaesthesist 2015 · 64:190–196 A.R. Heller · J. Heger · M. Gama de Abreu · M.P. Müller DOI 10.1007/s00101-015-0005-y Department of Anaesthesia and Intensive Care Medicine, Department of Anesthesiology and Critical Care Received: 8 August 2014 Medicine, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany Revised: 16 December 2014 Accepted: 17 December 2014 Published online: 11 March 2015 © The Author(s) 2015. This article is published with open access at Springerlink.com Cafedrine/theodrenaline in anaesthesia Influencing factors in restoring arterial blood pressure

Both general and regional anaesthe- able effects in patients with chronic isch- ulty, Fetscherstrasse 74, Dresden, Germa- sia are associated with a high rate of aemic heart disease [11, 15]. In addition, ny (EK255122004, 17.01.2005). The re- sympathicolysis-induced hypoten- cafedrine/theodrenaline combination cords from 353 consecutive anaesthe- sion that requires fast-acting and re- seems to offer benefits from a metabolic sia patients at our institution who re- liable anti-hypotonic agents to stabi- standpoint because of the lower lipolytic ceived cafedrine/theodrenaline were col- lise blood pressure. For decades hy- effect compared with catecholamines, par- lected and retrospectively evaluated. Pa- potension was avoided by the provi- ticularly under hypoxic conditions in acute tients were included in the study between sion of excessive fluid preload, how- myocardial infarction or shock [21]. July and November 2007, irrespective of ever, this practice faces increasing Although cafedrine/theodrenaline is the type of surgery, and received cafe- criticism [3]. In Germany, cafedrine/ widely accepted in the management of hy- drine/theodrenaline to manage hypoten- theodrenaline (Akrinor®) is approved potensive states in anaesthesia, intensive sion during anaesthesia. To reflect a re- as an anti-hypotensive agent along- care and emergency medicine [1, 6, 16], al-life cross-section of patients in a Ger- side a few other agents. few pharmacodynamic data have been man hospital, patients from the following published [13], and it is therefore impor- departments were included: orthopae- Background tant to collect data under routine clinical dics, trauma surgery, neurosurgery, vis- practice conditions. Cafedrine/theodren- ceral- thoracic and vascular surgery, gyn- Cafedrine/theodrenaline was introduced aline is routinely administered at our in- aecology, urology, oral and facial surgery in Germany in 1963, and pre-clinical da‑ stitution to patients in whom a quick and and eye surgery. ta showed a beta-adrenergic and an alpha- sustained MAP increase for 15–20 min is All patients fasted 2 h prior to induc- adrenergic component [22, 25, 26]. The net warranted and feasible with a single drug tion and received 7.5 mg midazolam OD effect is beta-adrenergic [25]. The combi- administration and without the vasopres- (Dormicum, Roche, Grenzach-Wyhlen, nation preparation increases mean arte‑ sor side effect of bradycardia; during these Germany) 45 min prior to arrival in the rial pressure (MAP), cardiac stroke vol- 15–20 min, fluid volume can be balanced. operating theatre. Concomitant medica- ume and cardiac output [18, 25]. Com- Gender-related differences in the ED50 of tion, including anti-hypertensives such as pared to alpha-adrenergic sympathomi- cafedrine/theodrenaline have previously beta-blockers, was continued as indicat- metic agents, cafedrine/theodrenaline was been reported by our group [13]. To con- ed by the standard operating procedures shown to cause less deterioration of renal, firm and expand on this observation un- of the department. A 5-lead electrocardio- cerebral and coronary perfusion [5]. In ad- der routine anaesthesia conditions, the gram, including measurement of segmen- dition, clinical practice with alpha-adren- time to 10 % increase in MAP after ad- tal ST depression (II, aVF, V5), and pulse ergic sympathomimetic agents requires ministration of cafedrine/theodrenaline oximetry was recorded. Non-invasive os- measures to control refectory critical bra- was examined. We hypothesized that gen- cillometric blood pressure was monitored dycardia, for example with atropine [7]. A der, heart failure and use of beta-blockers in 5 min intervals on the right upper arm study in dogs demonstrated that increased influence the effectiveness of cafedrine/ (IntelliVue, MP70, Philips, Böblingen, myocardial oxygen consumption caused theodrenaline. Germany). Values were manually trans- by positive inotropic cafedrine/theodren‑ ferred to anaesthesia protocols. The fol- aline effects are compensated for by en- Methods lowing data were recorded: age, gender, hanced coronary perfusion, increasing the height, body weight, current beta-blocker myocardial oxygen supply [9]. The phar- This study was approved by the Institu- therapy, American Society of Anesthesiol- macologic properties of this drug combi tional Review Board at the University ogists physical status and individual dosage nation may explain the distinctly favour- Hospital Carl Gustav Carus Medical Fac- of cafedrine/theodrenaline per injection.

190 | Der Anaesthesist 3 · 2015 In patients with ≥ 5 % drop in MAP 85 female male p=0.04 GLM cafedrine/theodrenaline was adminis-

80 tered to maintain MAP within a 20 % drop from baseline. We chose the 5 % drop in MAP as the inclusion criterion 75 to raise awareness that hypotension even in this range may be associated with late 70 complications. Timing and doses were recorded in anaesthesia protocols. The ob- 65 servation period in this study was limited

MAP [mmHg] to 30 min after the drop in MAP because 60 the variability of factors affecting MAP, such as additional volume therapy, ongo- 55 ing blood loss and the use of other drugs increases with time. Individual dosage 50 was defined in accordance with a previous Baseline 0510 15 20 25 30 dose-finding study, in which the ED50 of Time [min] cafedrine to achieve a 10 % MAP increase within 10 min was 0.53 mg/kg [13]. Fig. 1 8 Effects of cafedrine/theodrenaline on mean arterial pressure (MAP, mean ± SE) injected at time point 0 (reference value) in male and female patients. Both MAP drop and increase were statis- Administration of cafedrine/ tically significant (p < 0.001, paired t-test), as was the between-group comparison with general linear theodrenaline model (GLM) according to two-way analysis of variance (ANOVA) (p = 0.04)

An ampoule of 2 ml cafedrine/theodren- 90  female male aline (Akrinor , AWD.pharma GmbH p=0.668 GLM 85 & Co. KG, Dresden, Germany) contains 200 mg cafedrinhydrochloride, 10 mg 80 theodrenalinehydrochloride, 0.4 mg sodi- 75 umdisulfite, ethanol 96 %, glycerol 85 %, sodium acetate 3 H2O, acetic acid 99 % 70 and water. To enable fairly precise dos- 65 ing, 2 ml of cafedrine/theodrenaline were

t rate [bpm] diluted in 8 ml of saline to a total of 10 ml, 60 as suggested in the prescribing informa- Hear 55 tion. Throughout the manuscript doses are given for the cafedrine component of 50 the mixture. Due to the fixed milligram 45 ratio of 1:20, the dosage of theodrenaline can be calculated by dividing the respec- 40 Baseline 0510 15 20 25 30 tive cafedrine dose by 20. Time [min] Endpoints Fig. 2 8 Effects of cafedrine/theodrenaline on heart rate (mean ± SE) injected at time point 0 (reference value) in male and female patients. The difference between genders was not significant The primary endpoint was time to 10 % (p = 0.668), while the heart rate difference over time was statistically significant (p < 0.001) increase in MAP after administration of cafedrine/theodrenaline. Other study General anaesthesia was induced with Germany) in O2/N2O (35 %/60 %). Pa- endpoints were stability of heart frequen- 1.5 mg/kg propofol (Propofol 1 %, Fre tients were mechanically ventilated with cy and time to onset of effect dose rela- senius-Kabi, Bad Homburg, Germany) a minute volume adequate to maintain tive to gender, beta-blocking agents and  and 0.5 µg/kg sufentanil (Sufenta Jans- end-tidal pCO2 of 36–40 mmHg at a fresh the presence of heart failure (NYHA ≥ 1). sen-Cilag, Neuss, Germany). Tracheal in- gas flow of 1 l/min (Primus, Dräger, Lü‑ tubation was facilitated by 0.5 mg/kg ro- beck, Germany). Neuraxial anaesthesia Statistical analysis curonium (Esmeron, Organon, Ober- (spinal anaesthesia, epidural anaesthesia) schleißheim, Germany). General anaes- was performed with approved local an‑ Mean arterial blood pressure was calcu- thesia was maintained with desflurane aesthetics in awake seated patients [19]. lated as MAP = diastolic + (systolic-dia- (Suprane, Baxter, Unterschleißheim, stolic)/3. All data were anonymised and

Der Anaesthesist 3 · 2015 | 191 Abstract · Zusammenfassung

Anaesthesist 2015 · 64:190–196 DOI 10.1007/s00101-015-0005-y © The Author(s) 2015. This article is published with open access at Springerlink.com

A.R. Heller · J. Heger · M. Gama de Abreu · M.P. Müller Cafedrine/theodrenaline in anaesthesia. Influencing factors in restoring arterial blood pressure

Abstract Background. Hypotensive states that re- included in the study. The time to 10 % in- kg (cafedrine)/89.0 ± 83.5 µg/kg (theodren- quire fast stabilisation of blood pressure can crease in MAP, dosage of cafedrine/theodrenaline)] compared with healthy patients occur during anaesthesia. In 1963, the 20:1 aline, volume loading, blood pressure and [1.16 ± 0.77 mg/kg (cafedrine)/58.0 ± 38.5 µg/ mixture of cafedrine/theodrenaline (Akri- heart rate were monitored over time. kg (theodrenaline)] (p = 0.005). Concomitant nor®) was introduced in Germany for use in Results. Patients were a mean (standard de- medication with beta-blocking agents signif- anaesthesia and emergency medicine in the viation) of 64.4 ± 15.1 years old with a base- icantly prolonged the time to 10 % MAP in- first-line management of hypotensive states. line MAP of 82 ± 14 mmHg, which dropped crease [9.0 ± 7.0 vs. 7.3 ± 4.3 min (p = 0.008)]. Though on the market for many years, few to a mean of 63 ± 10 mmHg during anaes- Conclusion. Cafedrine/theodrenaline quick- pharmacodynamic data are available on this thesia without gender differences. Cafedrine/ ly restores MAP during anaesthesia. Female combination net beta-mimetic agent. theodrenaline (1.27 ± 1.0 mg/kg; 64 ± 50 µg/ gender is associated with higher effective- Aim. This study aimed to examine the drug kg) significantly increased MAP (p < 0.001) by ness, while heart failure and beta-blocker ad- combination in real-life clinical practice and 11 ± 16 mmHg within 5 min, reaching peak ministration lower the anti-hypotonic effect. recorded time to 10 % mean arterial blood values within 17.4 ± 9.0 min. Heart rate was Prospective studies in defined patient popu- pressure (MAP) increase and heart rate. Fur- not affected in a clinically significant man- lations are warranted to further characterise thermore, potential factors that influence ner. Cafedrine/theodrenaline induced a 10 % the effect of cafedrine/theodrenaline. drug effectiveness under anaesthesia were MAP increase after 7.2 ± 4.6 min (women) assessed. and after 8.6 ± 6.3 min (men) (p = 0.018). In- Keywords Methods. Data were collected within a dependent of gender, the dose of cafedrine/ Cafedrine/theodrenaline drug combination · standardised anaesthesia protocol. A to- theodrenaline required to achieve the ob- Hypotension · Heart frequency · Beta-blocker tal of 353 consecutive patients (female/ served MAP increase of 14 ± 16 mmHg at effects · Heart failure male = 149/204) who received cafedrine/ 15 min was significantly different in pa- theodrenaline after a drop in MAP ≥ 5 % were tients with heart failure [1.78 ± 1.67 mg/

Cafedrin/Theodrenalin in der Anästhesie. Faktoren, die die Wirksamkeit bei der Wiederherstellung des Blutdrucks beeinflussen

Zusammenfassung Hintergrund. Cafedrin/Theodrenalin (Akri- Cafedrin/Theodrenalin (1,27 ± 1,0 mg/ Gleichzeitige Medikation mit Betablock- nor®) wird in Deutschland für die Therapie kg/64 ± 50 µg/kg) erhöhte den MAP inner- ern verlängerte die Zeit bis zum 10 % MAP- von Blutdruckabfällen in Anästhesie und Not- halb von 5 min um 11 ± 16 mmHg (p < 0,001). Anstieg [9,0 ± 7,0 vs. 7,3 ± 4,3 min (p = 0,008)]. fallmedizin verwendet. Der maximale MAP war nach 17,4 ± 9,0 min Schlussfolgerung. Theodrenalin/Cafe- Ziel der Arbeit (Fragestellung). Die Studie erreicht; die Herzfrequenz wurde nicht drin stellt den MAP nach Blutdruckabfällen untersucht potentielle Faktoren, die die Wirk- im klinisch signifikanten Maß verändert. schnell wieder her ohne die Herzfrequenz samkeit des Arzneimittels beeinflussen. Cafedrin/Theodrenalin induzierte einen klinisch relevant zu verändern. Das Medika- Material und Methoden. Patientendaten 10 % MAP-Anstieg nach 7,2 ± 4,6 min bei ment zeigt eine höhere Wirksamkeit bei Frau- wurden mittels Anästhesie-Protokollen ge- Frauen und nach 8,6 ± 6,3 min bei Männern en, während Herzinsuffizienz und Betablo- sammelt. 353 Patienten (weiblich/männlich (p = 0,018). Unabhängig vom Geschlecht cker den Effekt schwächen. = 149/204), die Cafedrin/Theodrenalin nach waren die Dosen von Cafedrin/Theodren- einem Abfall des mittleren arteriellen Blut- alin, die zu dem beobachteten MAP-An- Schlüsselwörter drucks (MAP) ≥ 5 % erhielten, wurden einbe- stieg um 14 ± 16 mmHg nach 15 min füh- Cafedrin/Theodrenalin · Blutdruckabfall · zogen. rten, signifikant unterschiedlich zwisch- Herzinsuffizienz · Betablocker-Effekte · Ergebnisse. Die Patienten waren 64,4 ± 15,1 en Patienten mit und ohne Herzinsuffizienz Herzfrequenz Jahre alt und hatten einen Ausgangs-MAP (1,78 ± 1,67 mg/kg (Cafedrin)/89,0 ± 83,5 µg/ von 82 ± 14 mmHg, der während der Anäs- kg (Theodrenalin) vs. 1,16 ± 0,77 mg/kg thesie unabhängig von Geschlecht auf einen (Cafedrin)/58,0 ± 38,5 µg/kg (Theodrenalin), Mittelwert von 63 ± 10 mmHg abfiel. p = 0,005).

analysed using the Statistical Package for ment analyses, followed by Sidak alpha Data are expressed as mean ± SD. To Social Sciences for Windows, version 17.0 adjustment for multiple comparisons. A support readability and interpretation in (SPSS, Inc., Chicago, IL, USA). The pri- paired t-test served for analysing point to . Figs. 1 and 2, data are presented as mean mary study hypothesis was tested using a point changes in haemodynamics. To en- ± SE. A p-value of < 0.05 was considered Kaplan–Meier analysis followed by a log- sure equal distribution of risk factors be- statistically significant. rank test. General linear model statistics tween the observed cohorts, categorical according to a two-way analysis of vari- variables were compared with χ2 statistics. ance were applied for repeated measure-

192 | Der Anaesthesist 3 · 2015 Table 1 Demographic baseline characteristics and treatment (mean ± SD) the time to peak MAP did not differ in a Women (n = 149) Men (n = 204) p-value gender-related manner (. Table 2). Age (years) 65.6 ± 16.6 63.6 ± 13.8 n.s. Weight (kg) 69.6 ± 18.4 81.3 ± 15.4 0.001 Cafedrine/theodrenaline in ASA class 2.4 ± 0.7 2.5 ± 0.6 n.s. patients with heart failure Heart failure NYHA ≥ 1 [n (%)] 35 (23.5 %) 32 (15.7 %) n.s. Current beta-blocker therapy [n (%)] 50 (33.6 %) 61 (29.9 %) n.s. The time to highest MAP was lon- Heart failure NYHA ≥ 1 and beta-blocker therapy 18 (12.1 %) 18 (8.8 %) n.s. ger for the 67 patients with heart fail- [n (%)] ure than for patients without heart prob- Score by Canadian Cardiovascular Society 0.2 ± 0.5 0.1 ± 0.4 n.s. lems (p = 0.007) (. Fig. 4). In addition, Volume load with crystalloids (ml) 481 ± 293 493 ± 287 n.s. the dose (mg/kg body weight) to achieve Baseline MAP (mmHg) 81.8 ± 12.8 82.2 ± 14.5 n.s. MAP increase in a similar range at 15 min MAP after decrease (mmHg); reference 62.4 ± 8.9 63.8 ± 11.4 n.s. (by 14 ± 16 mmHg in heart failure patients Dosage Akrinor® (cafedrine mg/kg)a 1.3 ± 1.0 1.2 ± 1.0 n.s. and by 14 ± 14 mmHg in healthy patients) ASA American Society of Anesthesiologists, NYHA New York Heart Association, MAP mean arterial pressure were 1.78 ± 1.67 mg/kg in patients with aCafedrine:theodrenaline fixed milligram ratio = 20:1 heart failure and 1.16 ± 0.77 mg/kg in the healthy cohort (p = 0.005). This difference Table 2 Gender-related pharmacodynamic effects of cafedrine/theodrenaline (mean ± SD) was independent of gender. Women (n = 149) Men (n = 204) p-value 10 % MAP increase (min) 7.2 ± 4.6 8.6 ± 6.3 0.018 Cafedrine/theodrenaline in Time to maximum MAP effect (min) 17.0 ± 9.1 17.7 ± 9.0 n.s. patients with beta-blocking agents

Table 3 Conversion table for cafedrine/theodrenaline dosages into ml of standard dilutions Concomitant medication with be- Akrinor® ampoules 1 1/2 1/4 ta-blocking agents significantly pro- Cafedrine (mg) 200 100 50 longed the time to 10 % increase in MAP (n = 111, 9.0 ± 7.0 vs. 7.3 ± 4.3 min, Theodrenaline (mg) 10 5 2.5 p = 0.008) (. Fig. 5). Factors potentially Akrinor® solution undiluted (ml) 2 1 0.5 affecting the effectiveness of beta-stim- Akrinor® 1 ampoule diluted to 10 ml (ml) 10 5 2.5 ulants such as the extent of volume load Mean study dosage Akrinor® per 75 kg BW (amp)a 0.48 (492 ± 288 ml without beta-blocking aStudy mean dosage used was 1.3 ± 1.0 mg/kg (Cafedrine), 64 ± 50 µg/kg (Theodrenaline) agents and 475 ± 289 ml with beta-blocking agents) prior to blood pressure drop Results The highest MAP values were achieved did not differ between the groups. 17.4 ± 9.0 min after the drop and admin- Data were collected for 353 consec- istration of 1.27 ± 1.0 mg cafedrine/kg, Discussion utive anaesthesia patients (mean age independent of gender. For ease of trans- 64.4 ± 15.1) at a single institution who re- ferring applied cafedrine/theodrenaline Risks of hypotonia ceived cafedrine/theodrenaline to treat dosages into the reader’s clinical practice, during anaesthesia hypotensive states during surgery be- . Table 3 gives the relevant standard dos- tween July and November 2007. Demo- es, dilutions and relations to body weight. Induction of anaesthesia induces sym- graphic characteristics, baseline values Heart rates before the drop in MAP were pathicolysis, regardless of the type of an- and treatment are presented in . Table 1. a mean of 71 ± 18 and 67 ± 19 bpm after aesthesia, whether general or neuraxial, 172 and 181 patients received general and the drop (p < 0.001). and poses a risk of hypotension, in par neuraxial anaesthesia, respectively. ticular when the administration of in- The MAP dropped from a mean base- Cafedrine/theodrenaline travenous fluids is restricted [12, 17, 27]. line value of 82 ± 14 to 63 ± 10 mmHg effectiveness according to gender The dilation of resistance and capacitance (equivalent to 78 ± 12 % of the baseline vessels in the blocked area, with a subse- level; p < 0.001). MAP increase after 5 min Heart rates did not differ significantly be- quent decrease of pressure in the system- was also statistically significant (p < 0.001), tween genders (. Fig. 2). After the drop ic and pulmonary circulation, leads to a however mean baseline MAP values and in blood pressure cafedrine/theodrena- reduction in cardiac preload and after- the drop during surgery did not differ be- line induced a 10 % increase in MAP sig- load, posing a risk of cerebral or myocar- tween genders (. Fig. 1, . Table 2). MAP nificantly earlier in women 7.2 ± 4.6 vs. dial ischaemia as well as acute renal failure increased by 11 ± 16 mmHg (p < 0.001) 8.6 ± 6.3 min in men (p = 0.018) (. Table 2, [10, 14]. The use of balanced anti-hypo- 5 min after administration of cafedrine/ . Fig. 3), however, the duration of the tonic agents such as cafedrine/theodren- theodrenaline, while heart rates remained pressure-elevating effect as assessed by aline may be beneficial when combined at a mean of 66 ± 18 bpm over 20 min. with gentle volume loading, especially in

Der Anaesthesist 3 · 2015 | 193 Originalien

clude a broad range of patients that had a 1,0 ≥ 5 % blood pressure drop to represent a female real-life population, regardless of underlying conditions. The range of the drop in 0,8 blood pressure may vary in relation to the male underlying disease; this study focuses on the therapy of the hypotensive states. 0,6 Blood pressure restoration with p=0.018 log rank test pure alpha- or beta-adrenergic 0,4 agents vs. cafedrine/theodrenaline

10% MAP increase reached Due to the limited half-life, bolus administration of catecholamines has only a 0,2 short-term circulatory effect [7]. More- over, bolus injection of pure alpha-ago- nists cause an undesirable direct increase 0,0 in peripheral resistance, resulting in ad- 0510 15 20 25 30 ditional energy-consuming wall tension Time to 10% MAP increase [min] in the myocardium [5] and bradycardia, necessitating additional pharmacologic Fig. 3 8 Kaplan–Meier analysis of the time to 10 % mean arterial pressure (MAP) increase in male treatment with atropine [7]. Alternative- (dotted line) and female (solid line) patients after cafedrine/theodrenaline injection at time point 0 ly, pure beta-mimetic drugs induce a de- (p = 0.018, log-rank test) layed increase in blood pressure, due to initial vascular beta2-stimulation and the dependency on vascular filling; as a con- 1,0 sequence, undesirable increases in heart rate are observed [18]. p=0.007 log rank test Here we show that the administration 0,8 of cafedrine/theodrenaline significantly increased MAP in both genders without affecting the heart rate in a clinically sig- 0,6 nificant manner. These observations are healthy in line with experimental investigations [9, 11] and small clinical studies [13, 24].

0,4 Affecting the effectiveness: gender, beta-blocking highest MAP increase reached heart agents and heart failure 0,2 insu ciency The time to 10 % MAP increase in this cohort was longer in men and in patients 0,0 who had previously received beta-block-

0510 15 20 25 30 ing agents. The more rapid increase in Time to highest MAP increase [min] MAP in women may be attributable to the lower cafedrine/theodrenaline ED50 Fig. 4 8 Kaplan–Meier analysis of the time to highest mean arterial pressure (MAP) after cafedrine/ [13] and/or the higher intravascular flu- theodrenaline injection at time point 0 in patients with heart failure (NYHA ≥ 1, dotted line) and id volume is observed in women [23] due healthy patients (solid line) (p = 0.007, log-rank test). Cases not reaching a MAP increase of 20 % with- to the higher level of endogenous oestro- in 30 min were censored gen and resulting increase in preload. The downregulation of beta-receptors in old- elderly patients [4, 28] and during more effectiveness of cafedrine/theodrenaline. er men [8] and oestrogen receptor-de- extensive surgical interventions [20]. A Here we performed more in-depth analy- pendent effect that protects women from pilot study [13] suggested that male gen- ses (Kaplan–Meier analyses) using an in- left ventricular hypertrophy and conges- der, heart failure and beta-blocking agents dependent patient population to further tive heart failure [2] might represent con- are factors that negatively influence the elucidate the influences. We aimed to in- tributing factors as well. Although poten-

194 | Der Anaesthesist 3 · 2015 Acknowledgements. This study was funded 1,0 solely from institutional sources. Author Axel R. Heller received project funding (REF 13) from AWD. no beta blockers pharma GmbH & Co. KG, Dresden, Germany. Editorial assistance for manuscript preparation was provided by Physicians World Europe GmbH, Mannheim, 0,8 on beta blockers Germany, with financial support from Teva GmbH, Ulm, Germany. Compliance with ethical 0,6 guidelines p=0.008 log rank test Disclaimers. This work represents part of author Julia Heger’s doctoral thesis. 0,4 Open Access. This article is distributed under the

10% MAP increase reached terms of the Creative Commons Attribution License which permits any use, distribution, and reproduc- 0,2 tion in any medium, provided the original author(s) and the source are credited.

Conflict of interest. Julia Heger, Marcelo Gama 0,0 de Abreu, Michael P. Müller declare no conflict of interest. 0510 15 20 25 30 Time to 10% MAP increase [min] References

Fig. 5 8 Kaplan–Meier analysis of the time to 10 % mean arterial pressure (MAP) increase after cafe- 1. Aniset L, Konrad C, Schley M (2006) Ephedrine as drine/theodrenaline injection at time point 0 in patients with (dotted line) and without (solid line) cur- alternative to Akrinor in regional obstetric anes- rent beta-blocker therapy (p = 0.008, log-rank test) thesia. Anaesthesist 55:784–790 2. Babiker FA, Lips D, Meyer R, Delvaux E, Zandberg P, Janssen B, van Eys G, Grohe C, Doevendans PA tially not relevant under day-to-day cir- fied patient populations are certainly war- (2006) Estrogen receptor {beta} protects the mu- cumstances, during acute sympathicoly- ranted. rine heart against left ventricular hypertrophy. Ar- sis-dependent hypotension these factors terioscler Thromb Vasc Biol 26:1524–1530 3. Brandstrup B, Tonnesen H, Beier-Holgersen R, [2, 8] could have a clinical effect and at Conclusion for clinical practice Hjortso E, Ording H, Lindorff-Larsen K, Rasmus- least partially explain the gender-related sen MS, Lanng C, Wallin L, Iversen LH, Gramkow difference in the time to effect after cafe- 55 Cafedrine/theodrenaline results in a CS, Okholm M, Blemmer T, Svendsen PE, Rotten- sten HH, Thage B, Riis J, Jeppesen IS, Teilum D, drine/theodrenaline administration. The rapid haemodynamic effect on blood Christensen AM, Graungaard B, Pott F (2003) Ef- effect of concomitant beta-blocker thera- pressure without affecting heart rate fects of intravenous fluid restriction on postopera- py on the effectiveness of cafedrine/theo- to a clinically significant extent. tive complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded drenaline is not surprising, given the pre- 55Male gender, heart failure and the multicenter trial. Ann Surg 238:641–648 dominantly beta-mimetic effects of this previous administration of beta- 4. Buggy DJ, Power CK, Meeke R, O’Callaghan S, Mo- drug combination [24, 25] Patients with blocking agents negatively affect the ran C, O’Brien GT (1998) Prevention of spinal anaesthesia-induced hypotension in the elderly: i.m. heart failure required longer to reach the effectiveness of cafedrine/theodren- methoxamine or combined hetastarch and crystal- maximum MAP and required higher dos- aline. loid. Br J Anaesth 80:199–203 es of cafedrine/theodrenaline. Apparently 55Prospective studies to characterise 5. Carl M, Alms A, Braun J, Dongas A, Erb J, Goetz A, Gopfert M, Gogarten W, Grosse J, Heller A, Her- patients with heart failure are not able to the effect of cafedrine/theodrenaline inglake M, Kastrup M, Kroner A, Loer S, Marggraf respond to stimulation by alpha- and be- in defined patient populations are G, Markewitz A, Reuter M, Schmitt DV, Schirmer ta-adrenergic agents [13]. warranted. U, Wiesenack C, Zwissler B, Spies C (2007) Guide- lines for intensive care in cardiac surgery patients: haemodynamic monitoring and cardio-circulato- Limitations ry treatment guidelines of the German Society for Corresponding address Thoracic and Cardiovascular Surgery and the Ger- man Society of anaesthesiology and intensive care This study has a number of limitations. Prof. Dr. A. R. Heller medicine. Thorac Cardiovasc Surg 55:130–148 The association between heart failure and Department of Anaesthesia 6. Clemens KE, Quednau I, Heller AR, Klaschik the use of beta-blockers and the influence and Intensive Care Medicine E (2010) Impact of cafedrine/theodrenaline Department of Anesthesiology (Akrinor(R)) on therapy of maternal hypotension of health status and gender on the type and Critical Care Medicine during spinal anesthesia for Cesarean delivery: a of anaesthesia (general vs. regional) ad- Medizinische Fakultät Carl retrospective study. Minerva Ginecol 62:515–524 7. Deakin CD, Nolan JP, Soar J, Sunde K, Koster RW, ministered may have introduced sourc- Gustav Carus Smith GB, Perkins GD (2010) European Resuscita- es of selection bias, especially in patients Technische Universität Dresden tion Council Guidelines for Resuscitation 2010 Sec- with heart failure receiving beta-blockers. Fetscherstr. 74, 01307 Dresden tion 4. Adult advanced life support. Resuscitation axel.heller@uniklinkum-dres- 81:1305–1352 Larger prospective and controlled stud- den.de ies with a more strictly defined and strati-

Der Anaesthesist 3 · 2015 | 195 Fachnachrichten

8. Fowler MB, Laser JA, Hopkins GL, Minobe W, Bris- 24. Sternitzke N, Schieffer H, Hoffmann W, Bette L Situation ländlicher Kliniken ist tow MR (1986) Assessment of the beta-adrener- (1976) Modification of the cardiovascular-dynamic gic receptor pathway in the intact failing human effect of Akrinor following the blockade of adren- kritisch heart: progressive receptor down-regulation and ergic beta receptors with propranolol. Verh Dtsch Rund 44% aller ländlichen Krankenhäuser subsensitivity to agonist response. Circulation Ges Inn Med 82(Pt 2):1132–1135 74:1290–1530 25. Sternitzke N, Schieffer H, Rettig G, Bette L (1984) schreiben Verluste. Nur etwas mehr als ein 9. Hahn N, Sternitzke N, Malotki B, Raqué B, Die Beeinflussung der Herz-Kreislauf-Dynamik Drittel erzielt positive Ergebnisse. Gut 40% Eichelkraut W, Forneck G (1985) Der Einfluß von durch die Theophyllin-Verbindung Cafedrin und der Kliniken erwarten für 2015 eine weitere Akrinor auf die Hämodynamik und die Myokard- Theodrenalin sowie durch ihre Kombination. Herz Verschlechterung ihrer Lage. Das ist das Er- durchblutung bei partiell ischämiegeschädigtem Kreislauf 8:401–412 gebnis einer Studie der BDO AG Wirtschafts- Herzen (kardiogener Schock). Akute Versuche am 26. Usichenko TI, Foellner S, Gruendling M, Feyerherd prüfungsgesellschaft in Zusammenarbeit narkotisierten Hund. Herz Kreislauf 9:464 F, Lehmann C, Wendt M, Pavlovic D (2006) Akrinor- mit dem Deutschen Krankenhausinstitut 10. Hartmann B, Junger A, Klasen J, Benson M, Jost A, induced relaxation of pig coronary artery in vitro is Banzhaf A, Hempelmann G (2002) The incidence transformed into alpha1-adrenoreceptor-mediat- (DKI). Anhaltender Kostendruck, Investi- and risk factors for hypotension after spinal anes- ed contraction by pretreatment with propranolol. tionsstau, Fachkräftemangel und demografi- thesia induction: an analysis with automated data J Cardiovasc Pharmacol 47:450–455 scher Wandel verursachen auf dem Land collection. Anesth Analg 94:1521 27. Veering BT (2006) Hemodynamic effects of central weit größere Probleme als in Großstädten 11. Heller A, Grosser KD (1974) Hämodynamische Un- neural blockade in elderly patients. Can J Anaesth und Ballungsgebieten. Die Sicherung der tersuchungen an Infarktkranken nach intravenöser 53:117–121 Wirtschaftlichkeit, der Erhalt der Investi- Applikation von Akrinor. Med Welt 25:1890–1892 28. Yap JC, Critchley LA, Yu SC, Calcroft RM, Derrick tionsfähigkeit und der sich verschärfende 12. Heller AR, Litz RJ, Djonlagic I, Manseck A, Koch T, JL (1998) A comparison of three fluid-vasopres- Fachkräftemangel sind derzeit die größten Wirth MP, Albrecht DM (2000) Combined anesthe- sor regimens used to prevent hypotension during sia with epidural catheter. A retrospective analy- subarachnoid anaesthesia in the elderly. Anaesth Herausforderungen für die ländlichen Kran- sis of the perioperative course in patients ungoing Intensive Care 26:497–502 kenhäuser. Hier sind innovative Konzepte radical prostatectomy. Anaesthesist 49:949–959 und ein tiefgreifender Strukturwandel ge- 13. Heller AR, Radke J, Koch T (2008) Proof of effica- fragt. Dabei wächst die Bedeutung gerade cy and dose-response relationship of Akrinor® in der ländlichen Kliniken derzeit signifikant, patients during general and regional anaesthesia. denn Defizite in der ambulanten ärztlichen Anasth Intensivmed 49:308–317 Kommentieren Sie Versorgung sorgen für steigende Patien- 14. Klasen J, Junger A, Hartmann B, Benson M, Jost A, Banzhaf A, Kwapisz M, Hempelmann G (2003) Dif- diesen Beitrag auf tenzahlen in den Notaufnahmen. Wichtig fering incidences of relevant hypotension with springermedizin.de in der aktuellen Lage sind den befragten combined spinal-epidural anesthesia and spinal Krankenhäusern gesundheitspolitische anesthesia. Anesth Analg 96:1491 Strukturmaßnahmen für den ländlichen 7 Geben Sie hierzu den Beitragsti- 15. Klein O (1964) Zur Behandlung des akuten Kre- Raum, wie etwa der Ausbau von Kliniken zu islaufversagens in der operativen Medizin. Med tel in die Suche ein und nutzen Sie regionalen Gesundheitszentren, die Versor- Klinik 59:1879–1882 anschließend die Kommentarfunk- gungsprozesse sektorübergreifend steuern 16. Koch T, Wenzel V (2006) Alte Medikamente und tion am Beitragsende. und integrieren. Den höchsten Anteil länd- neue Zulassungssverfahren: Akrinor bleibt verkeh- rsfähig und ein Nachzulassungsantrag für Arginin licher Krankenhäuser haben die östlichen Vasopressin ist gestellt. Anaesthesist 55:708–710 Bundesländer (Mecklenburg-Vorpommern 17. Morgan P (1994) The role of vasopressors in the 97%, Thüringen 90%, Brandenburg 86%, management of hypotension induced by spinal Sachsen-Anhalt 76%, Sachsen 96%). Auch and epidural anaesthesia. Can J Anaesth 41:404– in Schleswig-Holstein stellen sie mit 69% 413 die Mehrzahl der Kliniken, ebenso in Nieder- 18. Müller H, Brähler A, Börner U, Boldt J, Stoyanov M, sachsen mit 54%. Gerade dort stehen die Hempelmann G (1985) Hämodynamische Verän- derungen nach der Bolusgabe verschiedener Va- ländlichen Krankenhäuser aktuell vor den sopressiva zur Blutdruckstabilisierung bei Peridu- größten Schwierigkeiten. ralanästhesie. Reg Anaesth 8:43–49 19. Panousis P, Heller AR, Koch T, Litz RJ (2009) Epidur- Quelle: BDO, www.bdo.de al ropivacaine concentrations for intraoperative analgesia during major upper abdominal surgery: a prospective, randomized, double-blinded, placebo-controlled study. Anesth Analg 108:1971–1976 20. Ponnudurai RN, Koneru B, Akhtar SA, Wachsberg RH, Fisher A, Wilson DJ, de la Torre AN (2005) Vaso- pressor administration during liver transplant surgery and its effect on endotracheal reintubation rate in the postoperative period: a prospective, randomized, double-blind, placebo-controlled trial. Clin Ther 27:192–198 21. Rettig G, Sternitzke N, Schieffer H, Hoffmann W, Bette L (1976) Einfluß einer blutdruckwirksamen Substanz auf die Stoffwechselsubstrate im Blut bzw. Serum. Arzneimittelforschung 26:1223–1227 22. Sakai K, Yasuda K, Taira N, Hashimoto K (1969) Al- pha-adrenergic blocking action of norephedrinet- heophylline (NET) observed in the renal vascular response. Jpn J Pharmacol 19:194–198 23. Stachenfeld NS, Taylor HS (2004) Effects of estrogen and progesterone administration on extracel- lular fluid. J Appl Physiol 96:1011–1018

196 | Der Anaesthesist 3 · 2015